Camptothecins are a new class of cytotoxic agents, which have been undergoing both preclinical and clinical testing against various solid tumors. The nuclear enzyme topoisomerase I (Topo I), along with the other topoisomerases, functions to resolve topological problems during DNA replication. These enzymes are the target for camptothecin and its derivatives. These agents are derivatives of an extract from the Chinese tree Camptotheca acuminata, and were originally shown to be active against L1210 murine leukemia (Wall, M. E., Wani, M. C., CoY, C. E., Palmer, K. H., MCPhail, A. T. and Sim, G. A.: Plant antitumor agents. 1. The isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibitor from Camptotheca acuminata, J. Chem. Soc., 88:3888, 1966). Further study confirmed that alkaline labile DNA (single strand) breaks were formed when camptothecin was added to cells in tissue culture and that the breaks rapidly resealed after removal of the drug. These DNA single strand breaks represent the nicks that form when camptothecin stabilizes the covalent adducts between genomic DNA and the reparative nuclear enzyme topo I (Horwitz, S. B., Change. C. S. C. K. and Grollman, A. P.: Studies on camptohtecin. 1. Effects on nucleic acid and protein synthesis. Mol. Pharmacol, 7:632, 1971; Hsiang, Y. H. and Liu, L. F: Identification of mammalian DNA topoisomerase I as an intracellular target of the anticancer drug Camptothecin. Cancer Res., 48: 1722, 1988). Early studies also showed maximal S-phase toxicity, and that the topo I-associated DNA single strand nicks led to the formation of more persistent double strand breaks which ultimately resulted in cell death. Camptothecins also appear to have other cytotoxic effects which amount for their activity in human tumor xenografts that typically have low S-phase fractions, though these effects are to be clearly defined.
A number of more soluble and less toxic analog of camptothecin have been developed, among them CPT-11 and topotecan hydrochloride are commercial products.
Topotecan hydrochloride is indicated for the treatment of metastatic carcinoma of the ovary after failure of initial or subsequent chemotherapy and for the treatment of small cell lung cancer sensitive disease after failure of first-line chemotherapy.
CPT-11 has been studied extensively in both preclinical and clinical trails and has shown good anti-tumor activity against a broad spectrum of experimental tumor models (Kunimoto, T., Nitta, K., Tanaka, T. Uchara, N., Baga, H., Takeuchi, M., Yokokura, T., Sawada, S., Miyasaka, T. and Mutai, M.: Antitumor activity of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin, against murine tumors. Cancer Res., 47:5944, 1987). It has recently received FDA approval for the treatment of colon cancer. Developed in 1983, CPT-11 is a semi-synthetic derivative of camptothecin which is, in effect, a prodrug converted to 7-ethyl-10-hydroxy-camptothecin (SN-38), following hydrolysis in the liver.
The intravenous drug form of CPT-11 is being developed for the treatment of colorectal cancer.
It is well known that parenteral administration of antitumor drugs such as, for example, camptothecin derivatives, is associated with some intrinsic disadvantages and drawbacks, e.g., patient discomfort or the requirement for the patient to travel to the physician's office for drug administration, with obvious results in patient inconvenience.
Thus the need has arisen to develop oral formulations of anti-tumor drugs that would allow to overcome the inconvenience and the discomfort of the patient that are associated with the parenteral way of administration.
Classical oral formulations are, for example, solid oral dosage forms, that are medication delivery systems presented as solid dose units readily administered by mouth. The group includes tablets, capsules, cachets and pills, as well as bulk or unit-dose powders and granules. The group constitutes the most popular form of presentation, and tablets and capsules account for the greatest number of preparations in this category.
It has long been known in the pharmaceutical industries that capsules are a convenient form for the oral administration of a variety of active agents because of their relative ease of manufacture (compared with other dosage forms such as tablets), flexibility of size and dose. Capsules have traditionally been used for powder or granule formulations but, in recent years, capsules have been adapted to contain the active ingredient in the form of paste, semi-solid or liquid formulation.
Since, for example, CPT-11 and topotecan hydrochloride are classified as class I cytotoxic agents, any form of leakage from the dosage form would present a safety concern.
The risk of leakage of a cytotoxic agent from a formulation as a tablet or powder-filled capsule, both during manufacturing and distribution, is extremely high.
Thus, in light of the above mentioned problem about the safe handling of these drugs, it is desirable to formulate them in a filling medium which is semi-solid and can be readily introduced and maintained into capsules without the expected problem of leakage.
In particular, a thermoplastic hot-melt type capsule formulation can be suitable for enhancing stability and for minimizing leakage concerns.
A problem to be solved when manufacturing a capsule filled with a semi-solid matrix, especially when it comprises a high concentration of an active such as a camptothecin derivative in the formulation, is the thickening, i.e. the increase of semi-solid matrix viscosity over time. The thickening of the semi-solid mass has repercussions not only on the manufacturing of the formulation (e.g. non-homogeneity of the formulation and impossibility to partition the formulation into capsules), but also on the reproducibility of the release profile of the active ingredient from the formulation itself.
A further problem to be faced regards the chemical and physical stability of the semi-solid filling matrix with aging. Several examples are described in the scientific literature, where semi-solid matrix systems change their physical state and their pharmaceutical characteristics with time and storage in different humidity/temperature conditions. As examples, SanVicente et al. clearly shows that the dissolution rate from glyceride matrices decreases with time (Proceedings of the 2nd World Meeting APGI/APV, Paris May 25–28, 1998, p. 261–2); and Sutananta W. et al. clearly shows the effect of aging on the physical properties of similar matrices, explored by DSC and tensile strength measurements (International Journal of Pharmaceutics, 111 (1994) 51–62).
Both the above mentioned problems were experienced when formulation activities for manufacturing a semi-solid matrix formulation for a camptothecin derivative were performed, especially when a semi-solid matrix comprises high concentrations of said camptothecin derivative.
There is therefore a need to find a formulation approach which allows to overcome thickening problems and to secure the maintenance of the physico-chemical characteristics of the semi-solid filling medium during manufacturing and storage.
It has now been surprisingly found that, by adding an effective amount of one or more excipients chosen from: a lecithin, a phospholipid, a pharmaceutical acceptable oil, a polyethylenglycol, and a saturated or unsaturated mono-, di- or triglyceride to the carrier matrix in which the camptothecin derivative is dispersed or dissolved, the above-mentioned problems can be solved.